A pro-apoptotic, biochemical role for the NF-κB-activating signaling pathway induced upon TCR restimulation in primed T cells

Friday, November 08, 2013 — Poster Session IV
2:00 p.m. – 4:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NIGMS	IMMUNO-15

Authors

C.L. Lucas
N.J. Siebenlist
M.J. Lenardo

Abstract

Homeostasis of T lymphocytes is tightly regulated to ensure adequate yet controlled immune responses to infectious agents. In stark contrast to the effects of TCR ligation in naïve T cells, restimulation of the TCR in activated, proliferating cells results in apoptotic cell death. A role for Fas and the extrinsic cell death pathway has long been appreciated; however, how the TCR triggers restimulation-induced cell death (RICD) of activated T cells is not well defined. We examined TCR signaling pathways mediating RICD and found that most pathways known to be involved in primary T cell activation are dispensable for RICD. However, one pathway, namely the PI3K-PDK1-PKC-TAK1-IKK kinase cascade, stood out as essential for TCR-induced RICD in human T cells. We further found that this cell death pathway does not appear to require NF-κB translocation into the nucleus or new protein translation. A notable characteristic of activated, proliferating T cells is that they contain significant levels of cleaved caspase 3 while remaining completely viable in the presence of IL-2. We hypothesize that a biochemical event downstream of TCR-induced IKK activation results in release of a brake restraining cell death in activated T cells in order to remove superfluous T lymphocytes in vivo.